Neurological Manifestations of Primary Immunodeficiencies.

Objective: Primary immunodeficiencies (PID) are a heterogeneous group of disorders with a variable clinical spectrum of manifestations. The central nervous system may be involved in PID with symptoms which may present initially or develop at later stages. The purpose of this study was to review the neurological manifestations of different PID syndromes. Materials & Methods: We focused on 104 selected studies on PID with certain neurological abnormalities which may accompany these disorders or may later signify a PID in their course. Results: Diverse neurological deficits accompanying certain PIDs may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of these patients. Conclusion: Early recognition and treatment is important to prevent or reduce future irreversible neurological sequelae. Therefore physicians should be aware of the neurological features accompanying PID.


Introduction
Primary immunodeficiencies (PID) are a heterogeneous group of 354 distinct disorders with 344 different gene defects (1) with a variable clinical spectrum of manifestations. A diagnosis of PID will often be considered with a predisposition to frequent, severe or unusual infections, autoimmune disorders and malignancies or allergic disorders (2).
PIDs have been classified practically according to the affected immune function to the following groups: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory disorders, complement deficiencies and phenocopies of PIDs

Materials & Methods
The last version of IUIS Primary Immunodeficiencies Committee Report (1) on Inborn Errors of Immunity was reviewed first to select certain PIDs with neurological manifestations. Then a review of literature was started according to specific PID associated with neurological manifestations with a focus on 104 selected studies.

Discussion
Immunodeficiencies affecting cellular and humoral immunity Severe combined immunodeficiencies defined by CD3 T cell lymphopenia

Adenosine Deaminase deficiency (ADA)
ADA is a ubiquitous enzyme in purine salvage pathway which is also expressed in both the peripheral and central nervous systems (6). ADA deficiency is caused by mutations in the ADA gene and is known as one of the most prevalent forms of severe combined immunodeficiencies (6). The most common manifestations include recurrent and opportunistic fungal, viral and bacterial infections, lymphopenia and failure to thrive (7). The main neurologic manifestations of these diseases result from accumulation of adenosine metabolites in basal ganglia and thalamus which are rich in adenosine receptors. These neurologic abnormalities include motor delay, hypotonia, mental retardation, learning disability, hyperactivity, attention deficit, behavioural abnormalities, reduced verbal Neurological Manifestations of Primary Immunodeficiencies expression, seizure and sensorineural deafness (4,8). One infant has been reported with nystagmus and difficulty in focusing gaze was found to have brain atrophy on MRI (9).

DNA Ligase IV deficiency
This autosomal recessive form of SCID is caused by an impairment of the DNA damage repair process with a pronounced radiosensitivity (10). DNA double-strand break repair via non-homologous end-joining (NHEJ) is involved in recombination of immunoglobulin and T-cell receptor genes.
Mutations in NHEJ components may lead to microcephaly and immunodeficiency (11).The neurological manifestations of this disease include microcephaly and developmental delay (12).

Cernunnos deficiency
This is another rare autosomal recessive form of SCID with severe T and B lymphopenia and dysgammaglobulinemia in addition to radiosensitivity caused by mutations in the CERNUNNOS or XRCC4-like factor (XLF).
Microcephaly and developmental delay are the prominent neurological features (4,8).

Ataxia-Telengiectasia
This autosomal recessive complex disorder with substantial severity in affected individuals (13) is characterized by ataxia, ocular and cutaneous telengiectasia, radiosensitivity, immunodeficiency,

Nijmegan Breakage Syndrome
This is a rare autosomal recessive, multisystemic disease of chromosomal instability presenting at birth with microcephaly but no additional neurologic manifestation (21). The mutated gene (NBS) has a critical role in responding to DNA damage. The defect leads to neuronal loss and microcephaly.
"Other manifestations include combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies and radiosensitivity" (21). Due to the radiation hypersensitivity in these patients, they are at increased risk of developing brain malignancies such as medulloblastoma (22).
These patients may exhibit progressive mental retardation which becomes more evident after age of 14 years (23). as well as brain developmental abnormalities including partial collosal agenesis, hydrocephaly, colpocephaly, neuronal migration abnormalities. The volume of the frontal lobe may be reduced and the gyral pattern may become simplified (24).

Instability and Facial Anomalies Syndrome
This genetic disease is due to a mutation in DNA

Riddle Syndrome
This syndrome is characterized by a defect in DNA damage response causing immunodeficiency and increased radiosensitivity accompanied by neurologic symptoms and growth delay due to an increased apoptosis and reduced proliferative capacity during brain development presenting as mild motor control and learning difficulties (28).

DiGeorge Syndrome
In

Schwachman-Diamond Syndrome
This is a multisystem disorder characterized by bone marrow failure, exocrine pancreatic insufficiency and metaphyseal chondrodysplasia. These features are attributed to mutation in SBDS gene (80).
However the precise pathologic pathways with the potential ability to disrupt the protein's function

Blau syndrome
This rare autosomal dominant syndrome clinically resembles early onset sarcoidosis characterized by granulomatous inflammation mostly involving joints, eyes and skin (95)(96)(97) and is caused by mutation in pattern recognition receptor NOD2 gene encoding a protein known as an intracellular sensor for bacterial products (98,99). This protein is activated after receiving signals from bacterial components resulting in activation of NFkB pathway which regulates innate responses (99).
Neurological manifestations are rare and include cranial neuropathies (hearing loss) and transient 6 th nerve palsy, cerebral vasculitis and cerebral infarction (100, 101).

Aicardi-Goutieres syndrome
This is a genetically determined encephalopathy

Authors' Contribution
All three authors were involved in data collection, and writing the article.